PACAP Protects Adult Neural Stem Cells from the Neurotoxic Effect of Ketamine Associated with Decreased Apoptosis, ER Stress and mTOR Pathway Activation.
PACAP Protects Adult Neural Stem Cells from the Neurotoxic Effect of Ketamine Associated with Decreased Apoptosis, ER Stress and mTOR Pathway Activation.
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PACAP可保护成年神经干细胞免受氯胺酮的神经毒性作用，与降低的凋亡，ER应激和MTOR途径激活相关。
DOI：
10.1371/journal.pone.0170496
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Lundberg M
中科院分区：
文献类型：
--
作者：
Mansouri S;Agartz I;Ögren SO;Patrone C;Lundberg M
氯胺酮给药是一种成熟的方法，可以在实验上模拟精神分裂症的某些方面。成人神经发生失调与精神障碍有关，包括精神分裂症。神经发生在氯胺酮诱导的表型中的潜在作用在很大程度上尚不清楚。人类遗传学研究的最新结果表明，垂体腺苷酸环化酶激活多肽(PACAP)基因是精神分裂症的危险因素。在实验性精神分裂症模型中，其对神经发生的潜在调节作用仍有待研究。我们的目的是确定氯胺酮是否影响成年神经干细胞(NSC)的活性。我们还研究了PACAP能否拮抗氯胺酮所介导的有害作用。从小鼠脑室下区分离神经干细胞，用氯胺酮加或不加PACAP。24小时后，用定量RT-PCR和Western印迹分析检测细胞存活率、可能参与的细胞凋亡、内质网应激、mTOR和AMPA通路的激活。我们发现氯胺酮通过增加细胞凋亡率、内质网应激和mTOR激活来损害NSC的活性。结果还表明，氯胺酮的作用是通过激活AMPA受体实现的。最后，我们证明了PACAP通过特异性激活PAC-1受体亚型来对抗氯胺酮引起的NSC活性下降。我们的研究表明，氯胺酮可能会对神经干细胞的活性产生负面影响，这可能对氯胺酮诱导的精神分裂症动物模型中精神分裂症表型的形成具有重要意义。通过激活PAC-1的神经保护作用表明，通过使神经发生正常化，可能成为治疗精神分裂症的新的药理靶点。
Ketamine administration is a well-established approach to mimic experimentally some aspects of schizophrenia. Adult neurogenesis dysregulation is associated with psychiatric disorders, including schizophrenia. The potential role of neurogenesis in the ketamine-induced phenotype is largely unknown. Recent results from human genetic studies have shown the pituitary adenylate cyclase-activating polypeptide (PACAP) gene is a risk factor for schizophrenia. Its potential role on the regulation of neurogenesis in experimental model of schizophrenia remains to be investigated. We aimed to determine whether ketamine affects the viability of adult neural stem cells (NSC). We also investigated whether the detrimental effect mediated by ketamine could be counteracted by PACAP. NSCs were isolated from the subventricular zone of the mouse and exposed to ketamine with/without PACAP. After 24 hours, cell viability, potential involvement of apoptosis, endoplasmic reticulum (ER) stress, mTOR and AMPA pathway activation were assessed by quantitative RT-PCR and Western blot analysis. We show that ketamine impairs NSC viability in correlation with increased apoptosis, ER stress and mTOR activation. The results also suggest that the effect of ketamine occurs via AMPA receptor activation. Finally, we show that PACAP counteracted the decreased NSC viability induced by ketamine via the specific activation of the PAC-1 receptor subtype. Our study shows that the NSC viability may be negatively affected by ketamine with putative importance for the development of a schizophrenia phenotype in the ketamine induced animal model of schizophrenia. The neuroprotective effect via PAC-1 activation suggests a potentially novel pharmacological target for the treatment of schizophrenia, via neurogenesis normalization.